EP0934312B1 - Piperazines 1,4-disubstituees - Google Patents

Piperazines 1,4-disubstituees Download PDF

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Publication number
EP0934312B1
EP0934312B1 EP97941884A EP97941884A EP0934312B1 EP 0934312 B1 EP0934312 B1 EP 0934312B1 EP 97941884 A EP97941884 A EP 97941884A EP 97941884 A EP97941884 A EP 97941884A EP 0934312 B1 EP0934312 B1 EP 0934312B1
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propyl
compound according
dibenzo
dihydro
piperazinyl
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EP0934312A1 (fr
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Rolf Hohlweg
Peter Madsen
Tine Krogh Jorgensen
Knud Erik Andersen
Brett Watson
Zdenek Polivka
Otylie Konigova
Alexandra Silhankova
Vladimir Valenta
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/78—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing seven-membered rings

Definitions

  • the present invention relates to novel N-substituted azaheterocyclic compounds in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, to the use of the compounds for preparing compositions for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, and to methods of treating said painful, hyperalgesic and/or inflammatory conditions.
  • the invention also relates to the use of the present compounds for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonising peptides like CGRP or amylin, the present compounds being known to interfere with neuropeptide containing C-fibres.
  • the present compounds can be used in the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) in order to improve the glucose tolerance as well as ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the nervous system exerts a profound effect on the inflammatory response.
  • Antidromic stimulation of sensory nerves results in localised vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151) and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro-intestinal and respiratory tracts.
  • inhibition of sensory nerve peptide release and/or activity may be useful in treatment of, for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine.
  • CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264 , E1-E10, 1993).
  • This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or ageing-associated obesity (Melnyk et al.
  • Obesity Res. 3 , 337-344, 1995 where circulating plasma levels of CGRP are markedly increased.
  • inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or ageing.
  • WO 9631498 and WO 9815548 disclose tricyclic compounds substituted by piperazine containing substituents useful in the treatment of conditions in which C-fibers play a pathophysiological role by eliciting pain or inflammation.
  • the present invention relates to compounds of the general formula I, wherein X, Y, Z, M 1 , M 2 , R 1 through R 12 , r and m are as defined in the detailed part of the present description.
  • the present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • a method of treating painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis
  • C-fibres play a pathophysiological role
  • a method of treating indications caused by or related to the secretion and circulation of insulin antagonising peptides like CGRP or amylin, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity may be described as the treatment of one of the above indications in a subject in need thereof, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the compounds of formula I may exist as geometric and optical isomers and all isomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention.
  • Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation of suitable salts.
  • the compounds of formula I exist as the individual geometric or optical isomers.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts or - when the carboxylic acid group is not esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66 , 2 (1977) which are known to the skilled artisan.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or by precipitation or crystallisation.
  • the compounds of formula I may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
  • C 1-6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1,2,2-trimethylpropyl.
  • C 1-6 -alkoxy refers to a straight or branched monovalent substituent comprising a C 1-6 -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • R 1 and R 2 are selected from hydrogen halogen, trifluoromethyl or C 1-6 -alkyl.
  • R 1 and R 2 are hydrogen, halogen or methyl.
  • X is selected from -CH 2 CH 2 -,-OCH 2 O-, -S-CH 2 - or -CH 2 -S-.
  • r is 1 or 2.
  • Z is selected from wherein M 1 and M 2 independently are C or N.
  • R 3 is hydrogen, trifluoromethyl, nitro or cyano.
  • R 4 is hydrogen, trifluoromethyl, nitro, cyano or (CH 2 ) m COR 11 .
  • m is 0 or 1.
  • R 11 is hydroxy
  • Preferred compounds of the present invention include:
  • novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of histamine induced paw oedema (Europ. J. Pharmacol. 279, 227-231, 1995) in which the novel compounds of formula I exhibit a potent inhibitory effect.
  • Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
  • Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, itching, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
  • neuropathy diabetic, post-traumatic, toxic
  • neuralgia rheumatoid arthritis
  • spondylitis gout
  • inflammatory bowel disease exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, g
  • the compounds of general formula I improve the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings.
  • the compounds of general formula I may be used in the treatment of NIDDM as well as ageing-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula I.
  • the compounds of formula I may be prepared by the following method:
  • a compound of formula II wherein R 1 , R 2 , X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an aza compound of formula III wherein Z is as defined above.
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride and a catalyst, e.g.
  • esters have been prepared in which R 11 is alkoxy
  • compounds of formula I wherein R 11 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
  • the carboxylic acid group can, for example, be esterified. Introduction and removal of such groups is described in "Protective Groups in Organic Chemistry” J.F.W. McOmie ed. (New York, 1973).
  • the rat histamine paw oedema test was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995). In brief 250-300 g male Sprague-Dawley rats were anaesthetized with pentobarbital sodium, and placed on a 32 degree (Celsius) heated table. Ten minutes later histamine (50 micoliter, 3 mg/ml) was injected in the right hind paw and 20 minutes hereafter the paw swelling was determined by water plethysmography (Ugo Basile). Test compounds were administered intraperitoneally at 15 minutes before the anaesthetics.
  • mice 16 weeks of age, where injected glucose (2g/kg) subcutaneously.
  • blood glucose was determined in tail venous blood by the glucose oxidase method.
  • glucose oxidase method was determined in tail venous blood by the glucose oxidase method.
  • mice were decapitated and trunk blood collected.
  • Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinking water (100 mg/l) for five days before the test.
  • the present invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary or parenteral e.g. rectal, depot, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral, nasal, pulmonary or parenteral e.g. rectal, depot, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilising agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques contains Core: Active compound (as free compound or salt thereof) 100 mg Colloidal silicon dioxide (Areosil®) 1.5 mg Cellulose, microcryst. (Avicel®) 70 mg Modified cellulose gum (Ac-Di-Sol®) Magnesium stearate 7.5 mg Coating: HPMC approx. 9 mg Mywacett® 9-40 T approx. 0.9 mg
  • the compounds of the invention may be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation, or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role such as e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, such as non-insulin-dependent diabetes mellitus (NIDDM) or ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • dosages suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.
  • Suitable dosage ranges varies as indicated above depending as usual upon the exact mode of administration, form in which administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
  • the organic layer was separated, washed with water (2 x 100 ml), acidified with 2 N hydrochloric acid and washed with water (2 x 50 ml).
  • the combined aqueous layers were made alkaline using a saturated solution of sodium hydrogen carbonate, and extracted with dichloromethane (200 ml).
  • the organic extract was dried (MgSO 4 ) and evaporated in vacuo.
  • N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mmol) was dissolved in 99.9 % ethanol (65 ml). Sodium methoxide (7.0 g, 130 mmol) was suspended in 99.9 % ethanol (70 ml) and added dropwise over 30 minutes. The resulting mixture was stirred for 30 minutes.
  • 1-Bromo-2-chloromethoxybenzene (26.1 g, 118 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974, 331-337) was added dropwise over 15 minutes. The reaction mixture was stirred for 2.5 h at room temperature, heated at reflux temperature for 2 h, and stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated.
  • HPLC retention time 18.42 minutes (5 ⁇ m C184 x 250 mm column, eluting with a 20-80% gradient of 0.1% trifluoriacetic acid/acetonitrile and 0.1% trifluoroacetic acid/water over 30 minutes at 30 °C.
  • the organic layer was extracted with 3 N hydrochloric acid (100 ml).
  • the acidic aqueous layer was made alkaline with 5 N sodium hydroxide (60 ml) to pH 12 and extracted with benzene (100 ml).
  • the benzene solution was dried (K 2 CO 3 ) and filtered over silica gel (12 g). Evaporation in vacuo provided an oil (2.98 g, 75 %). This was dissolved in ethanol (20 ml), acidified with hydrogen chloride in diethyl ether (3 mmol/ml, 8 ml) and precipitated with diethyl ether (20 ml).
  • HPLC retention time 23.82 minutes (5 ⁇ m C184 x 250 mm column, eluting with a 20-80% gradient of 0.1% trifluoriacetic acid/acetonitrile and 0.1% trifluoroacetic acid/water over 30 minutes at 30 °C.
  • 2-Fluoronitrobenzene (11.4 g, 81 mmol) was dissolved in dimethylsulfoxide (200 ml), and piperazine (56.4 g, 0.65 mol) and sodium carbonate (20.6 g, 0.2 mol) were added. The mixture was stirred at 130 °C for 16 h. After cooling, toluene (300 ml) was added and the mixture was washed with water (3 x 300 ml) and 1 N sodium hydroxide (300 ml). The organic phase was dried (MgSO 4 ) and concentrated in vacuo.

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Claims (30)

  1. Composé de formule I
    Figure 00650001
    dans laquelle
    R1 et R2 représentent chacun indépendamment de l'autre un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, hydroxy, alkyle en C1-6 ou alcoxy en C1-6 ; et
    X est un radical orthophénylène, -O-, -S-, -C(R6R7)-, -CH2CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2-(C=O)-, -(C=O)-CH2-, -CH2CH2CH2-, -CH=CH-, N(R8)-(C=O)-, -(C=O)-N(R8)-, -O-CH2-, -CH2-O-, -OCH2O-, -S-CH2-, -CH2-S-, -(CH2)N(R8)-, -N(R8)(CH2)-, -N(CH3)SO2-, -SO2N(CH3)-, CH(R10)CH2-, -CH2CH(R10), -(C=O)-, -N(R9)- ou -(S=O)-, où R6, R7, R8 et R9 représentent chacun indépendamment des autres un atome d'hydrogène ou un groupe alkyle en C1-6 ; et R10 est un groupe alkyle en C1-6 ou phényle ; et
    Y est >-N-CH2-, >CH-CH2-, >C=CH-, >CH-O-, où seul l'atome souligné participe au système cyclique ; et
    r vaut 1, 2 ou 3 ; et
    Z est choisi parmi
    Figure 00650002
    où
    M1 et M2 représentent chacun indépendamment de l'autre C ou N ; et
    R5 est un atome d'hydrogène ou un groupe alkyle en C1-6, phényle ou benzyle ; et
    R3 est un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, nitro ou cyano ; et
    R4 est un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, nitro, cyano, (CH2)mCOR11, (CH2)mOH ou (CH2)mSO2R11 où R11 est un groupe hydroxy, alcoxy en C1-6 ou NHR12, où R12 est un atome d'hydrogène ou un groupe alkyle en C1-6 ; et m vaut 0, 1 ou 2 ; ou
    R4 est choisi parmi
    Figure 00660001
    Figure 00660002
    ou l'un de ses sels acceptables d'un point de vue pharmaceutique.
  2. Composé selon la revendication 1, dans lequel R1 et R2 représentent chacun indépendamment de l'autre un atome d'hydrogène ou d'halogène, un groupe trifluorométhyle ou alkyle en C1-6, de préférence un atome d'hydrogène ou d'halogène ou le groupe méthyle.
  3. Composé selon l'une quelconque des revendications précédentes, dans lequel X est -CH2CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -OCH2O-, -S-CH2- ou -CH2-S-, de préférence -CH2CH2-, -OCH2O-, -S-CH2- ou -CH2-S-.
  4. Composé selon l'une quelconque des revendications précédentes, dans lequel Y est >N-CH2-, >C=CH- ou >CH-O-, où seul l'atome souligné participe au système cyclique.
  5. Composé selon l'une quelconque des revendications précédentes, dans lequel R vaut 1 ou 2.
  6. Composé selon l'une quelconque des revendications précédentes, dans lequel Z est choisi parmi
    Figure 00670001
    où M1 et M2 représentent chacun indépendamment de l'autre C ou N.
  7. Composé selon l'une quelconque des revendications précédentes, dans lequel R3 est un atome d'hydrogène ou un groupe trifluorométhyle, nitro ou cyano.
  8. Composé selon l'une quelconque des revendications précédentes, dans lequel R4 est un atome d'hydrogène, ou un groupe trifluorométhyle, nitro, cyano ou (CH2)mCOR11.
  9. Composé selon l'une quelconque des revendications précédentes, dans lequel m vaut 0 ou 1.
  10. Composé selon l'une quelconque des revendications précédentes, dans lequel R11 est un groupe hydroxy.
  11. Composé selon l'une quelconque des revendications précédentes, choisi parmi les composés suivants :
    acide 2-(4-(3-(12H-dibenzo[d,g][1,3]dioxocine-12-ylidène)-1-propyl)pipérazine-1-yl)-3-pyridinecarboxylique ;
    acide 2-(4-(3-(2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocine-12-ylidène)-1-propyl)pipérazine-1-yl)-3-pyridinecarboxylique ;
    acide 2-(4-(3-(12H-dibenzo[d,g][1,3,6]dioxazocine-12-ylidène)-1-propyl)pipérazine-1-yl)-3-pyridinecarboxylique ;
    acide 2-(4-(2-chloro-(12H-dibenzo[d,g][1,3,6]dioxazocine-12-ylidène)-1-propyl)pipérazine-1-yl)-3-pyridinecarboxylique ;
    1-3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptène-5-ylidène)-1-propyl)-4-(2-pyridyl)pipérazine ;
    acide 2-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptène-5-ylidène)-propyl)-1-pipérazinyl)-3-pyridine-carboxylique;
    acide 2-(4-(2-(10,11-dihydro-5H-dibenzo[b,f]azépine-5-yl)-1-éthyl-1-pipérazinyl)-3-pyridinecarboxylique ;
    acide 6-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]azépine-5-yl)-1-propyl-1-pipérazinyl)-2-pyridinecarboxylique ;
    acide 2-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]azépine-5-yl)-1-propyl-1-pipérazinyl)-3-pyridinecarboxylique ;
    acide 2-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]azépine-5-yl)-1-propyl-1-pipérazinyl)-5-pyridinecarboxylique ;
    acide 6-(4-(3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azépine-5-yl)-1-propyl-1-pipérazinyl)-3-pyridinecarboxylique ;
    1-3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptène-5-ylidène)-1-propyl)-4-(2-nitrophényl)pipérazine ;
    2-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptène-5-ylidène)-1-propyl-1-pipérazinyl)benzonitrile ;
    acide 2-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptène-5-ylidène)-propyl)-1-pipérazinyl)-benzoïque ;
    1-3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptène-5-ylidène)-1-propyl)-4-(3-trifluorométhyl-2-pyridyl)-pipérazine ;
    acide 2-(4-(2-(6,11-dihydro-dibenzo[b,e]thiépine-11-ylidène)éthyl)pipérazine-1-yl)-3-pyridinecarboxylique ;
    acide 2-(4-(2-(6,11-dihydro-dibenzo[b,e]-thiépine-11-ylidène)-1-propyl)-1-pipérazinyl)-3-pyridinecarboxylique ;
    acide 2-(4-(2-(6,11-dihydro-dibenzo[b,e]thiépine-11-yloxy)éthyl)-1-pipérazinyl)-3-pyridinecarboxylique ;
    6-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclpheptène-5-ylidène)-1-propyl)pipérazine-1-yl)-2-pyridinecarboxylique ;
    acide 6-(4-(3-(3-méthyl-10,11-dihydro-5H-dibenzo-[b,f]azépine-5-yl)-1-propyl-1-pipérazinyl)-2-pyridinecarboxylique ;
    acide 6-(4-(3-(dibenzo[d,g][1,3,6]dioxazocine-12-yl)-1-propyl)-pipérazine-1-yl)-pyridine-2-carboxylique ;
       ou l'un de ses sels acceptables d'un point de vue pharmaceutique.
  12. Composé selon l'une des revendications précédentes, qui est l'acide 2-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]-azépine-5-yl)-1-propyl)-1-pipérazinyl)-3-pyridine-carboxylique ou l'un de ses sels acceptables d'un point de vue pharmaceutique.
  13. Composé selon l'une des revendications précédentes, qui est le dihydrochlorure d'acide 2-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]-azépine-5-yl)-1-propy)}-1-pipérazinyl)-3-pyridine-carboxylique.
  14. Procédé de préparation d'un composé selon la revendication 1, caractérisé en ce qu'il consiste
    a) à faire réagir un composé de formule II
    Figure 00690001
    dans laquelle R1, R2, X, Y et r sont tels que définis ci-dessus et w est un groupe éliminable approprié tel qu'un groupe halogéno, p-toluènesulfonate ou mésylate, avec un composé de formule III
    Figure 00690002
    dans laquelle Z est tel que défini ci-dessus, pour former un composé de formule I.
  15. Composition pharmaceutique comprenant en tant que principe actif un composé selon l'une quelconque des revendications 1 à 13 en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  16. Composition pharmaceutique convenant au traitement des inflammations neurogènes, comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13, en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  17. Composition pharmaceutique convenant au traitement de la neuropathie, comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13, en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  18. Composition pharmaceutique convenant au traitement de la polyarthrite rhumatoïde, comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13, en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  19. Composition pharmaceutique convenant à la réduction de la glycémie et/ou à l'inhibition de l'activité du CGRP, comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13, en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  20. Composition pharmaceutique convenant au traitement de la migraine, comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13, en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  21. Composition pharmaceutique convenant au traitement du prurit, comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13, en même temps qu'un excipient ou diluant acceptables d'un point de vue pharmaceutique.
  22. Composition pharmaceutique selon les revendications 15 à 21, comprenant de 0,5 à 1000 mg du composé selon l'une quelconque des revendications 1 à 13 par dose unitaire.
  23. Composé pour utilisation dans un procédé de traitement d'une inflammation neurogène chez un patient ayant besoin d'un tel traitement, qui comprend l'administration à ce patient d'une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13.
  24. Composé pour utilisation dans un procédé de traitement d'une inflammation neurogène chez un patient ayant besoin d'un tel traitement, qui comprend l'administration à ce patient d'une quantité efficace d'un composé selon la revendication 22.
  25. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 pour préparer une composition pharmaceutique destinée au traitement de l'inflammation neurogène.
  26. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 pour préparer une composition pharmaceutique destinée au traitement de la neuropathie.
  27. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 pour préparer une composition pharmaceutique destinée au traitement de la polyarthrite rhumatoïde.
  28. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 pour préparer une composition pharmaceutique destinée à la réduction de la glycémie et/ou à l'inhibition de l'activité du CGRP.
  29. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 pour préparer une composition pharmaceutique destinée au traitement de la migraine.
  30. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 pour préparer une composition pharmaceutique destinée au traitement du prurit.
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US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
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US7820654B2 (en) * 2004-09-23 2010-10-26 Dr. Reddy's Laboratories Ltd. Pyrimidine compounds, process for their preparation and compositions containing them
FR2885616B1 (fr) * 2005-05-12 2007-06-22 Servier Lab Nouveaux derives de phenylpyridinylpiperazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
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WO2007056457A2 (fr) 2005-11-09 2007-05-18 Combinatorx, Incorporated Procedes, compositions et kits pour le traitement de pathologies
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